The mechanisms for neuronal degeneration in adult-onset central nervous system (CNS) diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), are not understood. Recent studies suggest that neurodegeneration in AD and ALS is apoptosis, occurring by programmed cell death (PCD). The investigator has developed an animal model to study neuronal apoptosis. Occipital cortex ablation in adult rat and mice, a model of axotomy and target deprivation, causes progressive retrograde neuronal degeneration in thalamus that is structurally apoptosis. This apoptosis is associated with accumulation of active mitochondria within the neuronal cell body and oxidative damage to DNA. The investigator proposes to evaluate the mechanisms for neuronal apoptosis in vivo. The investigator will test the hypothesis that apoptosis in neurons is signaled by subcellular translocation of Bcl-2 and Bax and release of cytochrome C from mitochondria, which correspond temporally with activation of caspases and DNA fragmentation factors. The participation Bcl-2 and Bax to the mechanisms for neuronal apoptosis will be determined by evaluating whether neuronal loss is reduced in lesioned transgenic mice overexpressing Bcl-2 and in mice deficient in Bax. The participation of mitochondrial permeability transition and cytochrome C release will be determined by post-injury treatment with the permeability transition blocker cyclosporin A. In addition, the investigator proposes that a signal for PCD in these neurons is oxidative stress. The investigator will test the hypothesis that retrograde neuronal death after axotomy is nuclear DNA damage-induced, p53-dependent apoptosis. The investigator will evaluate whether dying neurons sustain oxidative damage to DNA and proteins during the transition between chromatolysis and early apoptosis. The participation of oxidative stress as a mechanism for the induction of neuronal apoptosis in vivo after axotomy/target deprivation will be further examined by determining whether oxidative injury and apoptosis are attenuated in transgenic mice that are deficient in neuronal or inducible nitric oxide synthase and in mice that overexpress human wild-type superoxide dismutase 1. The dependence of this neuronal apoptosis on p53 will be evaluated in lesioned p53-deficient mice. The investigator will then use antioxidant therapies (Trolox and uric acid) to prevent or delay neuronal apoptosis. These studies will identify possible molecular mechanisms of neuronal apoptosis in vivo and could lead to the design of new therapeutic neuroprotection experiments critical for the future treatment of AD and ALS.